This invention relates to small molecule inhibitors of the IgE response to allergens that are useful in the treatment of allergy and/or asthma or any diseases where IgE is pathogenic.
An estimated 10 million persons in the United States have asthma, about 5% of the population. The estimated cost of asthma in the United States exceeds $6 billion. About 25% of patients with asthma who seek emergency care require hospitalization, and the largest single direct medical expenditure for asthma has been inpatient hospital services (emergency care), at a cost of greater than $1.6 billion. The cost for prescription medications, which increased 54% between 1985 and 1990, was close behind at $1.1 billion (Kelly, Pharmacotherapy 12:13S-21 S (1997)).
According to the National Ambulatery Medical Care Survey, asthma accounts for 1% of all ambulatory care visits, and the disease continues to be a significant cause of missed school days in children. Despite improved understanding of the disease process and better drugs, asthma morbidity and mortality continue to rise in this country and worldwide (U.S. Department of Health and Human Services; 1991, publication no. 91-3042). Thus, asthma constitutes a significant public health problem.
The pathophysiologic processes that attend the onset of an asthmatic episode can be broken down into essentially two phases, both marked by bronchoconstriction, that causes wheezing, chest tightness, and dyspnea. The first, early phase asthmatic response is triggered by allergens, irritants, or exercise. Allergens cross-link immunoglobulin E (IgE) molecules bound to receptors on mast cells, causing them to release a number of pre-formed inflammatory mediators, including histamine. Additional triggers include the osmotic changes in airway tissues following exercise or the inhalation of cold, dry air. The second, late phase response that follows is characterized by infiltration of activated eosinophils and other inflammatory cells into airway tissues, epithelial desquamonon, and by the presence of highly viscous mucus within the airways. The damage caused by this inflammatory response leaves the airways xe2x80x9cprimedxe2x80x9d or sensitized, such that smaller triggers are required to elicit subsequent asthma symptoms.
A number of drugs are available for the palliative treatment of asthma; however, their efficacies vary markedly. Short-acting xcex22-adrenergic agonists, terbutaline and albuterol, long the mainstay of asthma treatment, act primarily during the early phase as bronchodilators. The newer long-acting xcex22-agonists, salmeterol and formoterol, may reduce the bronchoconstrictive component of the late response. However, because the xcex22-agonists do not possess significant antiinflammatory activity, they have no effect on bronchial hyperreactivity.
Numerous other drugs target specific aspects of the early or late asthmatic responses. For example, antihistamines, like loratadine, inhibit early histamine-mediated inflammatory responses. Some of the newer antihistamines, such as azelastine and ketotifen, may have both antiinflammatory and weak bronchodilatory effects, but they currently do not have any established efficacy in asthma treatment. Phosphodiesterase inhibitors, like theophylline/xanthines, may attenuate late inflammatory responses, but there is no evidence that these compounds decrease bronchial hyperreactivity. Anticholinergics, like ipratopium bromide, which are used in cases of acute asthma to inhibit severe bronchoconstriction, have no effect on early or late phase inflammation, no effect on bronchial hyperreactivity, and therefore, essentially no role in chronic therapy.
The corticosteroid drugs, like budesonide, are the most potent antiinflammatory agents. Inflammatory mediator release inhibitors, like cromolyn and nedocromil, act by stabilizing mast cells and thereby inhibiting the late phase inflammatory response to allergen. Thus, cromolyn and nedocromil, as well as the corticosteroids, all reduce bronchial hyperreactivity by minimizing the sensitizing effect of inflammatory damage to the airways. Unfortunately, these antiinflammatory agents do not produce bronchodilation.
Several new agents have been developed that inhibit specific aspects of asthmatic inflammation. For instance, leukotriene receptor antagonists (ICI-204, 219, accolate), specifically inhibit leukotriene-mediated actions. The leukotrienes have been implicated in the production of both airway inflammation and bronchoconstriction.
Thus, while numerous drugs are currently available for the treatment of asthma, these compounds are primarily palliative and/or have significant side effects. Consequently, new therapeutic approaches which target the underlying cause rather than the cascade of symptoms would be highly desirable. Asthma and allergy share a common dependence on IgE-mediated events. Indeed, it is known that excess IgE production is the underlying cause of allergies in general and allergic asthma in particular (Duplantier and Cheng, Ann. Rep. Med. Chem. 29:73-81 (1994)). Thus, compounds that lower IgE levels may be effective in treating the underlying cause of asthma and allergy.
None of the current therapies eliminate the excess circulating IgE. The hypothesis that lowering plasma IgE may reduce the allergic response, was confirmed by recent clinical results with chimeric anti-IgE antibody, CGP-51901, and recombinant humanized monoclonal antibody, rhuMAB-E25. Indeed, three companies, Tanox Biosystems, Inc., Genentech Inc. and Novartis AG are collaborating in the development of a humanized anti-IgE antibody (BioWorld(copyright) Today, Feb. 26, 1997, p. 2) which will treat allergy and asthma by neutralizing excess IgE. Tanox has already successfully tested the anti-IgE antibody, CGP-51901, which reduced the severity and duration of nasal symptoms of allergic rhinitis in a 155-patient Phase II trial (Scrip #2080, Nov. 24, 1995, p.26). Genentech recently disclosed positive results from a 536 patient phase-II/III trials of its recombinant humanized monoclonal antibody, rhuMAB-E25 (BioWorld(copyright) Today, Nov. 10, 1998, p. 1). The antibody, rhuMAB-E25, administered by injection (highest dose 300 mg every 2 to 4 weeks as needed) provided a 50% reduction in the number of days a patient required additional xe2x80x9crescuexe2x80x9d medicines (antihistimines and decongestants), compared to placebo. An NDA filing for this product is projected to be in the year 2000. The positive results from anti-IgE antibody trials suggest that therapeutic strategies aimed at IgE down-regulation may be effective.
The present invention discloses several compounds that are active in down-regulating the IgE response to allergens and other provocative stimuli. One compound is disclosed for use in the treatment of a condition associated with an excess IgE level. The compound has a formula: 
wherein n is 1 to 3 and wherein R is H, alkyl, aryl, aminoalkyl, alkylaminoalkyl, substituted aryl or hydroxyalkyl. X, Y and Z are selected independently from the group consisting of H, alkoxy, aryloxy, alkyl, aryl, heteroaryl, hydroxyalkyl, carboxy, amine, alkylamino, cycloalkylamine, morpholine, thiomorpholine, alkoxycarbonyl, hydroxy, cyano, sulfonamide, alkylsulfonamide, substituted aryl, substituted heteroaryl, trifluoromethyl, trifluoromethoxy, nitro, halogen, thioalkyl, sulfoxyalkyl and sulfonylalkyl.
Another compound for use in the treatment of a condition associated with an excess IgE level is disclosed in accordance with the present invention. The compound has a formula: 
wherein X and Y are independently selected from the group consisting of H, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, benzyl, aryl, heteroaryl, hydroxy, carboxy, halogen, trifluoromethyl, trifluoromethoxy, carboxyalkyl, nitro, cyano, alkylsulfonyl, sulfonamide, alkylsulfonamides, amino, alkylamino, morpholine, thiomorpholine, alkylthio, sulfoxyalkyl and sulfonylalkyl. R1 and R2 are independently selected from the group consisting of H, alkyl, aryl, heteroaryl, carboxy, carboxyalkyl and carboxyaryl. R3 is selected from the group consisting of H, alkyl, aryl, CO-alkyl, CO-aryl and CO-heteroaryl.
Another compound for use in the treatment of a condition associated with an excess IgE level is disclosed in accordance with the present invention. The compound has a formula: 
wherein R1 and R2 are independently selected from the group consisting of H, alkyl, aryl, heteroaryl, carboxy, carboxyalkyl and carboxyaryl. R3 is selected from the group consisting of H, alkyl, aryl, CO-alkyl, CO-aryl, dialkylaminoalkyl, dialkylaminoalkylcarbonyl, substituted aryl, substituted heteroaryl and CO-heteroaryl, and R is selected from the group consisting of H, aryl, heteroaryl, substituted aryl and substituted heteroaryl.
Another compound for use in the treatment of a condition associated with an excess IgE level is disclosed in accordance with the present invention. The compound has a formula: 
wherein X and Y are independently H, halogens, alkyl, alkoxy, alkoxyalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, acylamino or alkylamino. R, Rxe2x80x2, Rxe2x80x3 and Rxe2x80x2xe2x80x3 are independently H, alkyl, alkoxyalkyl or dialkylaminoalkyl, and Rxe2x80x3 and Rxe2x80x2xe2x80x3 may independently also be a halogen.
A preferred variation on the cyclopropyl-substituted compound above is illustrated by the formula: 
wherein Z is H2 or O. X and Y are independently selected from the group consisting of H, halogens, alkyl, alkoxy, alkoxyalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, acylamino and alkylamino. R1 and R2 may be selected independently from the group consisting of H, alkyl, alkoxyalkyl, dialkylaminoalkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
A related compound for use in the treatment of a condition associated with an excess IgE level is disclosed in accordance with the present invention. The compound has a formula: 
wherein Z is H2 or O. X and Y are independently selected from the group consisting of H, halogens, alkyl, alkoxy, alkoxyalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino, acylamino and alkylamino. R1 and R2 are selected independently from the group consisting of H, alkyl, alkoxyalkyl, dialkylaminoalkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl.
Another compound for use in the treatment of a condition associated with an excess IgE level is disclosed in accordance with the present invention. The compound has a formula: 
wherein X and Y are selected independently from the group consisting of H, halogens, alkyl, alkoxy, aryl, amino, alkylamino, cycloalkylamino, morpholine, thiomorpholine, hydroxy, cyano, nitro, carboxy, alkoxycarbonyl, trifluoromethyl and trifluoromethoxy. R, Rxe2x80x2, Rxe2x80x3 and Rxe2x80x2xe2x80x3 are selected independently from the group consisting of H, alkyl, aryl, cycloalkyl, substituted cycloalkyl, polycycloalkyl, heteroaryl, arylalkyl, dialkylaminoalkyl and hydroxyalkyl.
Another compound for use in the treatment of a condition associated with an excess IgE level is disclosed in accordance with the present invention. The compound has a formula: 
wherein R is selected from the group consisting of aliphatic, aromatic, heterocyclic, substituted aromatic and substituted heterocyclic. X and Y are independently selected from the group consisting of H, halogen, alkyl, alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydroxy, nitro, trifluoromethyl, trifluoromethoxy and cyano.
Another compound for use in the treatment of a condition associated with an excess IgE level is disclosed in accordance with the present invention. The compound has a formula: 
wherein R1 is selected from the group consisting of H, halogen, alkoxy, alkyl, nitro, cyano, amino, CF3, OCF3 and hydroxy. R2 is selected from the group consisting of H, alkyl and aminoalkyl, R3 is H or alkyl, and R4 and R5 are independently selected from the group consisting of H, alkyl, aryl, heteroaryl, substituted aryl, substituted heteroaryl, cycloalkyl, aryl, aminocycloalkyl, hydroxyalkyl and substituted aryl.
Another compound for use in the treatment of a condition associated with an excess IgE level is disclosed in accordance with the present invention. The compound has a formula: 
wherein R and Rxe2x80x2 are selected independently from the group consisting of H, methyl, alkyl, aryl and substituted aryl. X, Y and Z are independently selected from the group consisting of H, halogen, alkyl, alkoxy, benzo, fused heterocyclic, CF3, OCF3, CN, COOH and COORxe2x80x3.
Another compound for use in the treatment of a condition associated with an excess IgE level is disclosed in accordance with the present invention. The compound has a formula: 
wherein the heterocyclic ring is selected from the group consisting of pyridines, quinolines, substituted pyridines and substituted quinolines. R and Rxe2x80x2 are independently selected from the group consisting of H, methyl, alkyl, aryl and substituted aryl.
Another compound for use in the treatment of a condition associated with an excess IgE level is disclosed in accordance with the present invention. The compound has a formula: 
wherein X and Y are independently selected from the group consisting of H, halogen, alkyl, alkoxy, aryl, substituted aryl, hydroxy, amino, alkylamino, cycloalkyl, morpholine, thiomorpholine, nitro, cyano, CF3 and OCF3. R is selected from the group consisting of H, CH3, C2H5, C3H7 and C4H9, and R1 and R2 are selected independently from the group consisting of H, methyl, ethyl, butyl, benzyl, substituted benzyl, dialkylaminoalkyl, alkyl, cycloalkyl, substituted cycloalkyl, polycycloalkyl, substituted fused cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl.
Another compound for use in the treatment of a condition associated with an excess IgE level is disclosed in accordance with the present invention. The compound has a formula: 
wherein X and Y are selected independently from the group consisting of H, alkyl, alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydroxy, halogen, NO2, CF3, OCF3, NH2, NHR3, NR3R4 and CN. Z is O, S, NH, and Nxe2x80x94Rxe2x80x2. R is selected from the group consisting of H, alkyl, halogen, alkoxy, CF3 and OCF3. Rxe2x80x2 is selected from the group consisting of H, alkyl, aminoalkyl, and dialkylaminoalkyl, and R1 and R2 are independently selected from the group consisting of H, alkyl, aminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, oxacycloalkyl and thiocycloalkyl.
Another compound for use in the treatment of a condition associated with an excess IgE level is disclosed in accordance with the present invention. The compound has a formula: 
wherein R1 and R2 are selected independently from the group consisting of H, alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl. X is selected from the group consisting of H, halogen, alkoxy, alkyl, CF3, NO2, CN and OCF3. R3 and R4 are selected independently from the group consisting of H, alkyl, cycloalkyl, oxacycloalkyl and thiocycloalkyl.
Another compound for use in the treatment of a condition associated with an excess IgE level is disclosed in accordance with the present invention. The compound has a formula: 
where R1, R2, R3, R4, R5 and R6 are selected independently from the group consisting of H, alkyl, cycloalkyl, oxacycloalkyl, thiocycloalkyl, aryl, arylalkyl, heteroaryl, heteroalkyl, substituted aryl and substituted heteroaryl.
Another compound for use in the treatment of a condition associated with an excess IgE level is disclosed in accordance with the present invention. The compound has a formula: 
wherein R1 and R2 are independently selected from the group consisting of H, alkyl, aryl, alkylaryl, substituted alkyl, substituted arylalkyl, dialkyl and aminoalkyl. R3 is selected from the group consisting of H, alkyl, aryl, halogen, CF3, OCF3, CN, NO2, NH2, NHR, carboxy, carboxyalkyl, alkoxy, heteroaryl, fused aryl and fused heteroaryl.
A method for treating a disease condition associated with excess IgE in a mammal is disclosed. The method comprises the step of administering to the mammal an IgE-suppressing amount of a pharmaceutical formulation comprising at least one IgE-suppressing compound from the above-disclosed small molecule families. In accordance with a variation of the method of treatment, the small molecule IgE-suppressing compound may be administered in conjunction with at least one additional agent, which is active in reducing a symptom associated with an allergic reaction. In one embodiment, the small molecule inhibitor may be mixed with at least one additional active ingredient to form a pharmaceutical composition. Alternatively, the small molecule inhibitor may be co-administered at the same time or according to different treatment regimens with the at least one additional active agent.
The at least one additional active ingredient may be a short-acting xcex22-adrenergic agonist selected from the group consisting of terbutaline and albuterol; a long-acting xcex22-adrenergic agonist selected from the group consisting of salmeterol and formoterol; an antihistamine selected from the group consisting of loratadine, azelastine and ketotifen; a phosphodiesterase inhibitor, an anticholinergic agent, a corticosteroid, an inflammatory mediator release inhibitor or a leukotriene receptor antagonist.
A dose of about 0.01 mg to about 100 mg per kg body weight per day of the small molecule IgE inhibitory compound is preferably administered in divided doses for at least two consecutive days at regular periodic intervals.
A method for treating a disease condition associated with excess IgE in a mammal is also disclosed which comprises the step of administering to the mammal an IgE-suppressing amount of a pharmaceutical formulation comprising at least one compound selected from the following group of compounds: 
wherein Z is selected from the group consisting of NH, O, S and Nxe2x80x94Rxe2x80x2;
wherein Rxe2x80x2 is selected from the group consisting of H, alkyl, aminoalkyl, and dialkylaminoalkyl;
wherein R1 is selected from the group consisting of H, Cl and SO2CH2CH3; and
wherein R2 is selected from the group consisting of H, Cl, CH3, OCH3, COOH and CF3, 
Other variations within the scope of the present invention may be more fully understood with reference to the following detailed description.